Chapter 9. First Principles Methods in Biology: From Continuum Models to Hybrid <i>Ab initio</i> Quantum Mechanics/Molecular Mechanics

Dreyer, J.; Brancato, Giuseppe; Ippoliti, Emiliano; Genna, Vito; Vivo, Marco De; Carloni, Paolo; Röthlisberger, Ursula

doi:10.1039/9781782626831-00294

Cited by 5 publications

(7 citation statements)

References 313 publications

(425 reference statements)

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“…Constant temperature simulations are achieved by coupling the system with a Nosé–Hoover thermostat at 500 cm –1 frequency. , The interactions between the MM and QM regions are coupled in a Hamiltonian scheme as discussed by Laio et al Notably, a rigorous Hamiltonian treatment of the electrostatic interaction between QM and MM regions is used, as in ref . The approach has been shown to accurately describe a variety of metal-dependent enzymes and, specifically, protein–DNA complexes. ,− …”

Section: Methodsmentioning

confidence: 99%

A Strategically Located Arg/Lys Residue Promotes Correct Base Paring During Nucleic Acid Biosynthesis in Polymerases

2018

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Polymerases (Pols) synthesize the double-stranded nucleic acids in the Watson-Crick (W-C) conformation, which is critical for DNA and RNA functioning. Yet, the molecular basis to catalyze the W-C base pairing during Pol-mediated nucleic acids biosynthesis remains unclear. Here, through bioinformatics analyses on a large data set of Pol/DNA structures, we first describe the conserved presence of one positively charged residue (Lys or Arg), which is similarly located near the enzymatic two-metal active site, always interacting directly with the incoming substrate (d)NTP. Incidentally, we noted that some Pol/DNA structures showing the alternative Hoogsteen base pairing were often solved with this specific residue either mutated, displaced, or missing. We then used quantum and classical simulations coupled to free-energy calculations to illustrate how, in human DNA Pol-η, the conserved Arg61 favors W-C base pairing through defined interactions with the incoming nucleotide. Taken together, these structural observations and computational results suggest a structural framework in which this specific residue is critical for stabilizing the incoming (d)NTP nucleotide and base pairing during Pol-mediated nucleic acid biosynthesis. These results may benefit enzyme engineering for nucleic acid processing and encourage new drug discovery strategies to modulate Pols function.

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Section: Methodsmentioning

confidence: 99%

A Strategically Located Arg/Lys Residue Promotes Correct Base Paring During Nucleic Acid Biosynthesis in Polymerases

2018

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“…Therefore, in order to simulate larger systems, hybrid approaches [12,[57][58][59] must be followed. In such a method, a small region of interest is simulated with ab initio molecular dynamics, while the rest of the molecular system is approximated with molecular mechanics:…”

Section: Hybrid Quantum Mechanics-molecular Dynamics Methodsmentioning

confidence: 99%

Computational Methods for Ab Initio Molecular Dynamics

Paquet

Viktor

2018

Advances in Chemistry

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Ab initio molecular dynamics is an irreplaceable technique for the realistic simulation of complex molecular systems and processes from first principles. This paper proposes a comprehensive and self-contained review of ab initio molecular dynamics from a computational perspective and from first principles. Quantum mechanics is presented from a molecular dynamics perspective. Various approximations and formulations are proposed, including the Ehrenfest, Born-Oppenheimer, and Hartree-Fock molecular dynamics. Subsequently, the Kohn-Sham formulation of molecular dynamics is introduced as well as the afferent concept of density functional. As a result, Car-Parrinello molecular dynamics is discussed, together with its extension to isothermal and isobaric processes. Car-Parrinello molecular dynamics is then reformulated in terms of path integrals. Finally, some implementation issues are analysed, namely, the pseudopotential, the orbital functional basis, and hybrid molecular dynamics.

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“…We also evaluated the energetics for the deprotonation of Lys131 via a second set of ab initio hybrid QM/MM simulations coupled to umbrella sampling. ,, We computed the in-line proton transfer from the protonated Lys131 to either the conserved Asp138 or a bulk water molecule. In both cases, the proton transfer event is described along a reaction coordinate (RC) defined by the difference between the length of the breaking N Lys –H Lys (i.e., r1) and forming H Lys –O Wat bonds (i.e., r2, Figure ).…”

Section: Resultsmentioning

confidence: 99%

“…Here, we tackle this challenge with a series of microsecond-scale force-field-based (FF) molecular dynamics (MD) simulations and free-energy calculations via the hybrid Car–Parrinello quantum mechanics/molecular mechanics (CP QM/MM) approach. − We describe a novel chemical mechanism where Lys131 acts in tandem with Tyr154 to transiently generate a cation−π interaction to promote the Exo−λ-mediated S N 2-type phosphoryl-transfer reaction for dsDNA hydrolysis.…”

Section: Introductionmentioning

confidence: 99%

A Transient and Flexible Cation−π Interaction Promotes Hydrolysis of Nucleic Acids in DNA and RNA Nucleases

2019

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Metal-dependent DNA and RNA nucleases are enzymes that cleave nucleic acids with great efficiency and precision. These enzyme-mediated hydrolytic reactions are fundamental for the replication, repair, and storage of genetic information within the cell. Here, extensive classical and quantum-based free-energy molecular simulations show that a cation−π interaction is transiently formed in situ at the metal core of Bacteriophage−λ Exonuclease (Exo−λ), during catalysis. This noncovalent interaction (Lys131−Tyr154) triggers nucleophile activation for nucleotide excision. Then, our simulations also show the oscillatory dynamics and swinging of the newly formed cation−π dyad, whose conformational change may favor proton release from the cationic Lys131 to the bulk solution, thus restoring the precatalytic protonation state in Exo−λ. Altogether, we report on the novel mechanistic character of cation−π interactions for catalysis. Structural and bioinformatic analyses support that flexible orientation and transient formation of mobile cation−π interactions may represent a common catalytic strategy to promote nucleic acid hydrolysis in DNA and RNA nucleases.

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Chapter 9. First Principles Methods in Biology: From Continuum Models to Hybrid Ab initio Quantum Mechanics/Molecular Mechanics

Abstract: First principles (i.e. non-empirical) simulations constitute nowadays a key tool in the investigation of biomolecular reactivity, photochemistry and spectroscopy. 1-7 They can be broadly divided in two categories, hybrid RSC Theoretical and Computational Chemistry Series No. 9

Cited by 5 publications

References 313 publications

A Strategically Located Arg/Lys Residue Promotes Correct Base Paring During Nucleic Acid Biosynthesis in Polymerases

A Strategically Located Arg/Lys Residue Promotes Correct Base Paring During Nucleic Acid Biosynthesis in Polymerases

Computational Methods for Ab Initio Molecular Dynamics

A Transient and Flexible Cation−π Interaction Promotes Hydrolysis of Nucleic Acids in DNA and RNA Nucleases

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